Neurotrophic mechanisms underlying the rapid and sustained antidepressant actions of ketamine

Abstract

Clinical and preclinical studies have demonstrated that depression, one of the most common psychiatric illnesses, is associated with reduced levels of neurotrophic factors, including brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), contributing to neuronal atrophy in the prefrontal cortex (PFC) and hippocampus, and reduced hippocampal adult neurogenesis. Conventional monoaminergic antidepressants can block/reverse, at least partially, these deficits in part via induction of BDNF and/or VEGF, although these drugs have significant limitations, notably a time lag for therapeutic response and low response rates. Recent studies reveal that ketamine, an N-methyl-d-aspartate receptor antagonist produces rapid (within hours) and sustained (up to a week) antidepressant actions in both patients with treatment-resistant depression and rodent models of depression. Rodent studies also demonstrate that ketamine rapidly increases BDNF and VEGF release and/or expression in the medial PFC (mPFC) and hippocampus, leading to increase in the number and function of spine synapses in the mPFC and enhancement of hippocampal neurogenesis. These neurotrophic effects of ketamine are associated with the antidepressant effects of this drug. Together, these findings provide evidence for a neurotrophic mechanism underlying the rapid and sustained antidepressant actions of ketamine and pave the way for the development of rapid and more effective antidepressants with fewer side effects than ketamine.

Keywords: BDNF; Depression; Ketamine; Rapid antidepressants; Synaptogenesis; VEGF-A.

Fig. 1.

Model for the cellular mechanisms underlying the rapid and sustained antidepressant actions of ketamine. Ketamine blockade of NMDARs on GABAergic interneurons results in disinhibition and a rapid glutamate burst that activates AMPARs. This leads to activation of L-type voltage-dependent Ca²⁺ channels (VDCCs) and Ca²⁺ influx that stimulates BDNF and VEGF release. BDNF and VEGF stimulate TrkB and Flk-1, respectively. Activation of TrkB and Flk-1 stimulates the mTORC1 signaling pathway which controls the translation and synthesis of synaptic proteins, including GluA1 and PSD95, that are required for increases in synaptogenesis and spine maturation. These cellular events are associated with the rapid and sustained antidepressant behavioral actions of ketamine. ADT, antidepressant; GABA_AR, GABA_A receptor.